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The mechanism of niacin-induced skin flushing ( adapted from Messamore et al 13 ). COX, cyclooxygenase; IL, interleukin; INF, interferon; PGD , prostaglandin D ; PGF prostaglandin F ; PLA , phospholipase A ; TNF, tumor necrosis factor. 2 2 2, 2 2 2
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The skin flush response to niacin is abnormally blunted among a subset of patients with schizophrenia (SZ), preferentially
associates with SZ compared to other mental illnesses, occurs frequently in nonpsychotic members of SZ-affected families,
appears heritable, and shows evidence of genetic association. The niacin response abnormality (NRA) may p...
Citations
... Disruption of lipid function is one of the components of SCZ pathogenesis [31]. Yao et al. demonstrated a direct link between abnormal phospholipid levels and disrupted neurochemical parameters, such as SCZ-associated abnormal dopamine and glutamate levels [32]. Phospholipid metabolism abnormalities occur during the progression of SCZ. ...
Background: Lipids are a crucial component of the human brain, serving important structural and functional roles. They are involved in cell function, myelination of neuronal projections, neurotransmission, neural plasticity, energy metabolism, and neuroinflammation. Despite their significance, the role of lipids in the development of mental disorders has not been well understood. Results: This review focused on the potential use of lipids as blood biomarkers for common mental illnesses, such as major depressive disorder, anxiety disorders, bipolar disorder, and schizophrenia. This review also discussed the impact of commonly used psychiatric medications, such as neuroleptics and antidepressants, on lipid metabolism. Conclusion: The obtained data suggested that lipid biomarkers could be useful for diagnosing psychiatric diseases, but further research is needed to better understand the associations between blood lipids and mental disorders and to identify specific biomarker combinations for each disease.
... Since significant cutaneous vasodilation can occur in the absence of visually detectable edema, some studies measure skin changes using Doppler flowmetry [20,40,41]. The use of specialized equipment is also associated with the measurement of skin color changes using optical reflection spectroscopy [42]. ...
... Still, in this case, niacin non-responders did not differ in age from responders [30]. Yao et al., examining the skin reaction with a laser doppler flowmeter in individuals diagnosed with SCH and BD, also proved that niacin response abnormality was not influenced by the age or race of the patients [41]. ...
... Based on clinical and theoretical considerations by David Horrobin, that prostaglandin deficiency is associated with patients diagnosed with SCH as well as those abusing alcohol, it is worth noting that the results of the Fiedler et al. study showed impaired skin reaction in NSFT in individuals addicted to alcohol [35,61,62]. Taking substance use into consideration, there are reports confirming that smoking cigarettes do not affect the NSFT results [41,46]. Likewise, Smesny et al. presented the results of the study that showed no observable effect on skin redness during the NSFT in cannabis users [42]. ...
The niacin skin flush test (NSFT) is a simple method used to assess the content of fatty acids in cell membranes and is a possible indicator of factors hidden behind various outcomes in patients. The purpose of this paper is to determine the potential usefulness of NSFT in mental disorder diagnostics along with the determination of factors that may affect its results. The authors reviewed articles from 1977 onwards, focusing on the history, variety of methodologies, influencing factors, and proposed mechanisms underlying its performance. Research indicated that NSFT could be applicable in early intervention, staging in psychiatry, and the search for new therapeutic methods and drugs based on the mechanisms of NSFT action. The NSFT can contribute to defining an individualized diet for patients and prevent the development of damaging disease effects at an early stage. There is promising evidence for supplementation with polyunsaturated fatty acids, which have a beneficial influence on the metabolic profile and are effective even in the subclinical phase of the disease. NSFT can contribute to the new classification of diseases and a better understanding of certain mental disorders' pathophysiology. However, there is a need to establish a validated method for assessing the NSFT results.
... This phenomenon is considered to be related to the membrane hypothesis of schizophrenia proposed by Horrobin [13,14]. There is at least one subtype of schizophrenia with a clinically significant membrane phospholipid signaling defect [51] that appears to be more likely to attenuate the response to niacin. Topical application of niacin to the skin activates a specific G-protein-coupled receptor, GPR109A (also known as HM74A) [36], which stimulates the activation of phospholipase A2 (PLA2) [48], resulting in the release of arachidonic acid (AA) from cell membranes, followed by cyclooxygenase-mediated conversion to vasodilatory prostaglandins, mostly vasodilatory prostaglandins D2 (PGD2) and E2 (PGE2) [32] (See Supplementary Figure S1). ...
... The association between niacin subsensitivity and the clinical features of schizophrenia has been inconsistent in the literature. A few studies [29,37,42] have found a significant correlation between niacin sensitivity and the severity of psychotic symptoms, but more studies [4,43,49,51] have failed to find a significant correlation. In an interesting study by Tavares et al. [49], they not only demonstrated that absent response to niacin is more frequent in patients with schizophrenia than in healthy individuals, but also found that a subgroup of patients with schizophrenia who underwent antipsychotic therapy exhibited conversion of absent niacin skin flushing to a positive flush response. ...
... Second, the niacin-induced flushing response, expressed as log 10 (EC 50 ) molar and MBF values, are presented as box plots (Fig. 1A, B) and compared using the nonparametric Mann-Whitney U test. According to Yao et al. [51], the ANR subgroup was defined as having a value above 90% of the log 10 (EC 50 ) molar value and lower than 60% of the MBF value in the HC group. A small group of ANR samples was identified in a scatter diagram (Fig. 1C). ...
Although the phenomenon of attenuated niacin response (ANR) has been widely replicated in some patients with first-episode psychosis (FEP), its relevance to the negative symptoms (NS) of psychosis remains unclear. Total of 240 patients with drug-naïve FEP and 101 healthy controls (HCs) were recruited, and 209 were followed up for 1 year. Psychotic symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS), and niacin-induced responses were measured using laser Doppler flowmetry. We calculated the log-transform EC50 [concentration of methyl nicotinate required to elicit a half-maximal blood flow (MBF) response] and MBF values. Core-NS was generated by factor analysis of the PANSS-NS subscale and cluster analysis to produce subtypes. Significant differences were found in the log10 (EC50) values between the FEP and HC groups (p < 0.001), supporting the ANR in patients with FEP. A higher NS severity was found in the ANR subgroup than that in other patients. Factor analysis determined that a two-dimensional model included core NS and rigidity of thinking. The log10 (EC50) value was significantly associated with only the core NS. Cluster analysis revealed three subtypes—36.7% (cluster-1, n = 88), 16.7% (cluster-2, n = 40), and 46.7% (cluster-3, n = 112). Cluster-2 characterized by extensive NS appeared to have a more remarkable ANR and less symptomatic improvement than those with other clusters during follow-up. No significant changes were found in the niacin response trajectories between the baseline and follow-up. Our findings indicate a significant correlation between ANR and core NS in patients with FEP. ANR may be a potential biomarker for certain subtypes with NS-dominated characteristics and poor symptomatic remission.
... Tao Chen, 1,2,3,4,5 Haichun Liu, 6,7 Renfang Tian, 8 Ranpiao Gan, 9 Wenzuo Xu, 1, 3 Tianhong Zhang, 9,10 Jijun Wang 9,11,12 IntroductIon Schizophrenia is a devastating mental disorder affecting 20 million people worldwide. 1 Early diagnosis is crucial for disease management and improvement in prognosis, and diagnostic biomarkers can serve as objective indicators for the early screening of the disease. ...
... 2 In particular, trait markers with endophenotypic characteristics 3 4 that can be applied in the premorbid phase to increase power by predicting the outcome of conversion to psychosis are desirable. Blunted skin flush response to niacin has been widely reported in patients with psychosis [5][6][7] and nonpsychotic first-degree relatives. 8 9 Attenuated niacin response in patients with psychosis has been consistently reported in previous studies, 6 10 and such abnormalities are heritable traits within psychosis-affected families. ...
... Blunted skin flush response to niacin has been widely reported in patients with psychosis [5][6][7] and nonpsychotic first-degree relatives. 8 9 Attenuated niacin response in patients with psychosis has been consistently reported in previous studies, 6 10 and such abnormalities are heritable traits within psychosis-affected families. 11 Other indirect evidence has shown that diminished flush responses are stable across time and depend on the stage of illness. ...
Background:
Impaired sensitivity of the skin flush response to niacin is one of the most replicated findings in patients with schizophrenia. However, prior studies have usually focused on postonset psychosis, and little is known about the clinical high-risk (CHR) phase of niacin sensitivity in psychosis.
Aims:
To profile and compare the niacin flush response among CHR individuals (converters and non-converters), patients with first-episode schizophrenia (FES) and healthy controls (HCs).
Methods:
Sensitivity to four concentrations (0.1-0.0001 M) of aqueous methylnicotinate was tested in 105 CHR individuals, 57 patients with FES and 52 HCs. CHR individuals were further grouped as converters and non-converters according to the 2-year follow-up outcomes. Skin flush response scores were rated on a 4-point scale.
Results:
Of the 105 CHR individuals, 21 individuals were lost during the study, leaving 84 CHR individuals; 16 (19.0%) converted to full psychosis at 2 years of follow-up. Flush response scores identified in the CHR samples were characterised as modest degree levels, intermediate between those of HC individuals and patients with FES. The flush responses in the CHR group mimicked the responses observed in the FES group at higher concentrations (0.01 M, 0.1 M) and longer time points (15 min, 20 min); however, these became comparable with the responses in the HC group at the shorter time points and at lower concentrations. The converters exhibited lower mean flush response scores than the non-converters.
Conclusions:
Attenuated niacin-induced flushing emerged during the early phase of psychosis. New devices should be developed and verified for objective quantification of skin responses in the CHR population.
... An attenuated niacin-induced flush response in schizophrenia has exhibited several characteristics that render it a potential endophenotype of schizophrenia [1][2][3] . The prevalence of the niacin response abnormality was higher in schizophrenia patients [4][5][6] , first-episode psychosis patients 7 , and ultra-high risk patients 8 than in healthy controls. ...
Despite the consistent finding of an attenuated niacin-induced flush response in schizophrenia, its long-term stability and relationship to the membrane polyunsaturated fatty acid (PUFA) levels remain unknown. We conducted niacin skin tests and measured the membrane PUFAs using gas chromatography among 46 schizophrenia inpatients and 37 healthy controls at the baseline and the 2-month follow-up. Attenuated flush responses were persistently observed in schizophrenia patients in both acute and partial remission states, whereas an increased flush response was found in the controls. A persistent decrease in both dihomo-gamma-linolenic acid and docosahexaenoic acid and an increased turnover of arachidonic acid (ARA) via endogenous biosynthesis were found in schizophrenia patients. A composite niacin flush score by combining those with a control-to-case ratio of >1.4 (i.e., scores at 5 min of 0.1 M, 0.01 M, and 0.001 M + 10 min of 0.01 M and 0.001 M + 15 min of 0.001 M) at the baseline was correlated positively with ARA levels among controls but not among schizophrenia patients, whereas the flush score at the 2-month follow-up was correlated positively with ARA levels among patients. The 2-month persistence of attenuated niacin-induced flush response in schizophrenia patients implies that the niacin skin test might tap a long-term vulnerability to schizophrenia beyond acute exacerbation.
... Third, the PLA2/COX pathway is involved in the niacin skin flush reaction. Skin flushing in response to niacin is abnormally blunted among a subset of patients with schizophrenia and is considered a potential marker for schizophrenia [18,19]. The biochemical basis of the niacin skin flush response is reasonably well understood. ...
Background
Schizophrenia (SZ) is a severe mental disease with highly heterogeneous clinical manifestations and pathological mechanisms. Schizophrenia is linked to abnormalities in cell membrane phospholipids and blunting of the niacin skin flush response, but the associations between these phenotypes and its molecular pathogenesis remain unclear. This study aimed to describe the PLA2/COX pathway, the key link between phospholipids and niacin flush, and to illustrate the pathogenic mechanisms in schizophrenia that mediate the above phenotypes.
Methods
A total of 166 patients with schizophrenia and 54 healthy controls were recruited in this study and assigned to a discovery set and a validation set. We assessed the mRNA levels of 19 genes related to the PLA2/COX cascade in leukocytes by real-time PCR. Plasma IL-6 levels were measured with an ELISA kit. Genetic association analysis was performed on PLA2G4A and PTGS2 to investigate their potential relationship with blunted niacin-skin response in an independent sample set.
Findings
Six of the 19 genes in the PLA2/COX pathway exhibited significant differences between schizophrenia and healthy controls. The disturbance of the pathway indicates the activation of arachidonic acid (AA) hydrolysis and metabolization, resulting in the abnormalities of membrane lipid homeostasis and immune function, further increasing the risk of schizophrenia. On the other hand, the active process of AA hydrolysis from cell membrane phospholipids and decreased transcription of CREB1, COX-2 and PTGER4 may explain the reported findings of a blunted niacin response in schizophrenia. The significant genetic associations between PLA2G4A and PTGS2 with the niacin-skin responses further support the inference.
Interpretation
These results suggested that the activation of AA hydrolysis and the imbalance in COX-1 and COX-2 expression are involved in the pathogenesis of schizophrenia and blunting of the niacin flush response.
Funding
This work was supported by the National Key R&D Program of China (2016YFC1306900, 2016YFC1306802); the National Natural Science Foundation of China (81971254, 81771440, 81901354); Interdisciplinary Program of Shanghai Jiao Tong University (ZH2018ZDA40, YG2019GD04, YG2016MS48); Grants of Shanghai Brain-Intelligence Project from STCSM (16JC1420500); Shanghai Key Laboratory of Psychotic Disorders (13DZ2260500); and Shanghai Municipal Science and Technology Major Project (2017SHZDZX01); China Postdoctoral Science Foundation (2018M642029, 2018M630442, 2019M661526, 2020T130407); Natural Science Foundation of Shanghai (20ZR1426700); and Startup Fund for Youngman Research at SJTU (19 × 100040033).
... Horrobin's theory is supported by post-mortem observational studies, which confirmed reduced levels of AA in patients with schizophrenia [6,7]. More and more studies indicate that the niacin test may be a simple, quick and non-invasive method to reveal disruptions in the metabolic pathway of fats [8][9][10][11][12]. A topical application of niacin to skin activates the G-coupled nicotinic acid receptors, which induces the activation of phospholipase A2 (PLA-2), the release of fatty acids (mainly AA, but also eicosapentaenoic acid-EPA) from cell membranes, and (via a mechanism mediated by COX-1 and COX-2) the formulation of prostaglandins (E2 and D2). ...
... What is more, the authors showed that the most useful parameter for distinguishing schizophrenic patients from healthy persons was the combination of variables-min/step value-which including both time and concentration at 6 min of 0.001 M, and at 21 min of 0.01 M-sensitivity was 92% and specificity 84% [10]. According to the Portland study, the blood flowmetry method indicated niacin response abnormality with a sensitivity of 32% and a specificity of 95%, for differentiating schizophrenia and healthy controls, and 32% and 87% respectively for differentiating schizophrenia and bipolar disorder patients [11]. Yao et al. pointed out that the niacin response abnormality predicted schizophrenia with 31% sensitivity and 95% specificity, compared to the healthy controls, and with 31% sensitivity and 97% specificity compared to the bipolar disorder individuals [11]. ...
... According to the Portland study, the blood flowmetry method indicated niacin response abnormality with a sensitivity of 32% and a specificity of 95%, for differentiating schizophrenia and healthy controls, and 32% and 87% respectively for differentiating schizophrenia and bipolar disorder patients [11]. Yao et al. pointed out that the niacin response abnormality predicted schizophrenia with 31% sensitivity and 95% specificity, compared to the healthy controls, and with 31% sensitivity and 97% specificity compared to the bipolar disorder individuals [11]. ...
Schizophrenia has been considered a disorder linked with faulty lipid homeostasis, and the proposed tool for assessment of these disruptions is the niacin skin flush test. The aims of the study were: 1. Create a new tool to analyze results of the niacin skin flush test more precisely and objectively. 2. Verify the utility of a self-created tool for differentiating between schizophrenia (SZ; n = 56), bipolar disorder (BD; n = 29) and healthy control (HC; n = 45) individuals. The proposed developed method, based on the Skin Reaction Measurement Computer System (SKINREMS), allows one to evaluate the response to the niacin skin flush test quickly and objectively. SKINREMS showed good accuracy in discriminating SZ from BD (with sensitivity 91% and specificity 72%), and SZ from HC (71% and 66%, respectively), and sufficient but not excellent accuracy in discriminating BD from HC (55% and 54%, respectively). The pathophysiological pathways and features shared by schizophrenia and bipolar disorder may be the reason for difficulties in fully discriminating between these two mental disorders using the niacin challenge test. The management of disruptions in the phospholipid metabolism and the inflammatory process could potentially become an individualized form of therapy in a subgroup of psychiatric patients.
... Many comprehensive reviews have focused on its relationship to schizophrenia (Buretic-Tomljanovic, Giacometti et al. 2008;Nadalin, Buretic-Tomljanovic et al. 2010). Moreover, it seems that niacin response abnormality has a high specificity for schizophrenia among those who have schizophrenia when compared to those who have bipolar disorder (Yao, Dougherty et al. 2016). ...
... Psychosis is a heterogeneous disease entity (Jablensky, 2006) in which altered lipid biosynthesis is one of several candidate pathophysiological mechanisms. Abnormal responses to a niacin skin flush test, indicative of alterations in lipid metabolism, are found in 30% of patients with schizophrenia (SCZ) and are also more prevalent in their healthy relatives (Messamore, 2017;Yao et al., 2016). Overlap between genetic polymorphisms associated with both SCZ and lipid metabolism has been demonstrated, implicating the involvement of lipid biology in the pathophysiology of SCZ (Andreassen et al., 2013). ...
Background:
Dyslipidemia and insulin resistance (HOMA-IR) are cardiovascular risk factors prevalent in patients with psychosis. Whether these factors are intrinsic or affected by lifestyle or antipsychotic medication (AP) is unclear. Therefore, we investigated lipid profiles, HOMA-IR, and psychotic phenotypes in patients aged 12-18 years with early-onset psychosis (EOP) with and without AP exposure.
Method:
We measured fasting total cholesterol (TC), high-density lipoprotein cholesterol (HDLC), triglycerides (TG), insulin, and glucose in patients with EOP (n = 39) and healthy controls (HC) (n = 66). Diet information was not available. Negative symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS). We used univariate analysis of variance to compare TC/HDL-C ratios and TG and HOMA-IR values, controlling for body mass index (BMI) and AP exposure. We assessed the explained variance of having EOP using multiple regression analysis.
Results:
Patients with and without AP exposure had significantly higher TC/HDL-C (p = 0.003, p = 0.029) and TG values (p < 0.001, p = 0.021) than HC. Significantly increased HOMA-IR scores were found only in AP-exposed patients (p = 0.037). EOP significantly increased the explained variance for TC/HDL-C and TG, but not for HOMA-IR. Patients with a PANSS negative score > 21 had significantly higher levels of TG than those with low scores (p = 0.032).
Conclusion:
Our results suggest that lipid alterations predate AP treatment in adolescents with EOP. Higher levels of negative symptoms and AP further increase metabolic risk. The preliminary findings propose that subclinical dyslipidemia may be intrinsic to EOP.
